2&#39;-keto-3, 4-imidazolido-2-omega-substituted alkyl thiophenes and process for obtaining same



Patented Apr. 4, 1950 ST-ITUTED ALKYL THIOPI-IENES AND PROCESS FOROBTAININGSAME Leeic; y, etroit, Mich, assignor mMB -k Davis & Company,Detroit, Mich., a corpora.

No Drawing.

This invention relates to a methodior the synthesis ot't-he recentlydiscovered biologically active compound ,known as biotin and certainanalogs thereof containing the same bicyclic ring system v as biotin.The inventionalso includes a new class orbiotin-like' compounds notpreviously described which can bem'ade iii-accordance with the newneth'odcfthe present invention, "[The' process of this inventionconsists in catalytically reducing the two ring double bonds-of acompound of the general formula,

to 35nd the alkylene residue,

' (-C1 ,H2n

may bestralghtor branched, ,and WhGI'G'Rl is a; radical of the class--COOI-I, COOM', -..'COOR.;;;alkoxy-, aralkoxy and arylioxy, B beinglower;alkylv and M' representing a salt-forming basidgroup or metalsuchas sodium 'orother-alkali..metal.- alkaline earth metal, ammonium'orsubstituted ammonium.

The above formulated. new; class of doubly unsaturated compounds are2-lieto-3,4-imidazolido- 2-w-substituted alkylthiophenes. Theirpreparation is described in copen'ding ap'plication of Lee C. Cheney andJohn Robert Piening, Serial No. 569,640, filed December 23, 1944, now U.S. Patent 2,466,004.

I have discovered that biotin type compounds canbe. prepared: by.catalytically hydrogenating theab ve formulated; starting, materials attheir -carboni.double' bonds by reactionwith I gen tft'emperature'sbetweenabout.1.00''C1 andftjllo? vC'Zjand under hyclrc'zgen pressures,he-

i tween'about 50 and'75'0 atmospheres in the presence of a sulfidecatalyst from the class consisting oifsulfides, oi molybdenum, nickel.cobalth tin The.hydrogenation can. be carried out on the liquid, solidor vaporized" forms ohms-"starting Application 'Februaryqil, 1945,Serial No. 577,155'

- sclaims. (01. 260-309) materials and in thepresence of. the. sulfide.catalystin the form of relativelylarge masses or in comminutedorpowderediorm, either in suspension in a substantially dry inert. organicsolvent or associated .withcatalyst carrier means such as alumina,asbestosor likeinert solid.

The following examples serve to illustrate the invention withoutlimiting. it to. the .particulardetails. of time,.[ temperature,materials and. other conditions specifically described therein.

' Example 1 A mixture of'2.,40"g. (0.01v mole). of 2,3g.4,'5,.-tetra;-dehydrobiotin, 500 ml; of purified dioxane and '80 g. of pulverizedmolybdenum trisulfide-alumina gel catalyst is rocked in an Adkinshydrogenator and heated from 200 C..-to 210 C. for five hours under ahydrogen pressure of 2700 lbs. per square inch. The cooled bomb isopened and the catalyst is removed by filtr-ation. The bomb and catalystare washed with 500 "ml. of warm absolute alcohol. Combined filtrate andwashings are dis.- tilled'under reduced pressure. The brown residuecontains d,l biotin and its stereoisorners' .A sample of'the'product'stimulates the growth. of L. arab'z'nosus,,amicrobiological testwhich shows the presence of biotin. or biotin-active compounds; Byfractional"crystallization of the brown residue from water or aqueous oranhydrous organic solvents, such as lower aliphatic alcohols, thepurified d,l-biotin, M. P. 232 C., is isolated.

'- imidazolido 2 y phenoxyprop ylthiophene, 600 ml.

of absolute alcohol and g. of pulverized molybdenum. trisulfide-aluminagel catalyst is rocked and heated in .an. Adkins"hydrogenator at atemperature ofIlQO-ZOO CI. and undera hydro.- gen pressure of 2600' lbs.per square inch for a period of twenty-four hours, After cooling, thebomb is opened and the catalyst is removed by filtration through afritted" glass funnel. The bomb and the catalyst arewashed with a totalof 400 ml. of warm absolute alcohol, in several portions. Combinedfiltrate and washings are distilled to dryness under reduced pressure.The light-brown solid residue consists mainly of 2'-pyltetraliydrothiophene. This product can be obtained in the form ofpure white crystals, by recrystallizing it several times from aqueous oranhydrous organic solvents such as methyl alcohol, ethyl alcohol orother lower aliphatic alcohol. It is useful as an intermediate for thepreparation of biotin.

Although ethyl alcohol and dioxane are used as solvents for the bicyclicsulfur compounds in the above examples, any other monohydroxy orpolyhydroxy alcohol or glycol such as methyl alcohol, propyl alcohol,isopropyl alcohol, ethylene glycol, propylene glycol and relatively lowmolecular weight alcohol ethers, such as ethylene glycol monomethyletheror ethylene or propylene glycol monoethyl ether, may be used as areaction medium.

The reaction medium is preferably kept near neutrality, although theprocess gives the desired hydrogenation even when somewhat alka line oracidic conditions are used.

I have found that sulfides of molybdenum,

such as molybdenum trisulfide or disulfide, are

especially good catalysts for the process of the present invention.However, the various su1.- fides of iron, cobalt, nickel and tin alsogive satisfactory results. In view of the known great instability of thesulfide linkage of the organic compounds utilized in this invention, itwas surprising to find that any of the catalysts men tioned would permitof hydrogenation of the "carbon-to-carbon double bonds withoutcompletely disrupting the carbon-sulfur heterocyclic ring. Instead ofhydrogenating thethiophene valeric acid or 2-y-phenoxypropylthiophenecompounds as described in the examples, any of the other compounds underthe general formula given above can be used whereby the tetrahydro-.genated compounds are obtained of formula,

- nificance already given. Thus, one could use the-2'-keto-3,4-imidazolido 2 'y benzyloxypropylthiophene described underExample 3 of said copending application, Serial No. 569,640, whereby thecorresponding tetrahydrogenated compound of formula,

is obtained. The latter compound, as well as the compound of Example 2above, is a member of the new class of compounds of the formula,

| H; CH-U Han-R:

where n is an integer from 1 to 8 inclusive and;

the alkylene residue (CnH2n-) is straight or branched chain and where R:is a member of the class alkoxy, cycloalkyl substituted alkoxy andcycloalkoxy radicals. The R2 group of these compounds difiers from thecarboxyl or related groups (COOM and COOR') present in biotin. These newcompounds are valuable as biotin-like compounds and also serve asintermediates for preparation of biotin itself. Biotin prepared asdescribed in Example 1 has the formula,

whereas the new compound of Eiiample 2 has the formula,

1. Process for the preparation of 2-keto-3,limidazolido-2-w-substitutedalkyl thiophenes which compriseshydrogenatingin the presence of a catalyst of the class consisting ofsulfides of molybdenum, nickel, cobalt, tin and iron, a compound offormula,

where n=1 to 8 and (--CnH2n) is an alkylene residue, and where R1 is aradical of the class consisting of COOH, COO(alkali metal), COO(alkalineearth metal) -COONHi, COO (lower alkyl), alkoxy, aralkoxy and aryloxy.

2. Process for the preparation of 2-keto-3,4'-imidazolido-Z-w-substituted alkyl thiophenes which compriseshydrogenatingin the presence of a catalyst of the class consisting ofsulfides of molybdenum, nickel, cobalt, tin and iron, a compound offormula. 1

3. Process for the preparation of 2'-keto-3,4- imidazolido 2w-substituted alkyl thiophenes which comprises hydrogenating, in thepresence of a sulfide of molybdenum, a compound of formula,

-(OHzh-C 0011 5. Process for the preparation of 2-keto-3,4imidazolido-Z-(w-carboxy-substituted) n butylthiophene which compriseshydrogenating, in the presence of a sulfide of molybdenum, the ringdouble bonds of a compound of formula,

6. Compounds of the formula,

0 II HN NH H+--cH H1O H-C,|Hz,.Ra

where R2 is a member of the class consisting of alkoxy, cycloalkylsubstituted alkoxy and. cycloalkoxy radicals and n is an integer from 1to 8 inclusive.

7. A compound of the formula,

8. A compound of the formula,

LEE C. CHENEY.

No references cited.

1. PROCESS FOR THE PREPARATION OF2''-KETO-3,4IMIDAZOLIDO-2-W-SUBSTITUTED ALKYL THIOPHENES WHICH COMPRISESHYDROGENATING, IN THE PRESENCE OF A CATALYST OF THE CLASS CONSISTING OFSULFIDES OF MOLYBDENUM, NICKEL, COBALT, TIN AND IRON, A COMPOUND OFFORMULA, WHERE N=1 TO 8 AND (-CNH2N-) IS AN ALKYLENE RESIDUE, AND WHERER1 IS A RADICAL OF THE CLASS CONSISTING OF -COOH, -COO(ALKALI METAL),-COO(ALKALINE EARTH METAL), -COONH4, -COO (LOWER ALKYL), ALKOXY,ARALKOXY AND ARYLOXY.